Early Detection of Pancreatic Cancer: Considerable Advances, but Still a Long Way to Go
Authors: Ruiyuan Xu, Chengcheng Wang, Yupei Zhao
Journal: Clinical Gastroenterology and Hepatology (2023)

We read with great interest the work by Haan et al.1Haan D. et al.Clin Gastroenterol Hepatol. 2023; 21: 1802-1809.e6Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar In this study, the authors developed an early detection pancreatic cancer (PaC) test based on 5-hydroxymethylcytosine differential profiling in plasma cell-free DNA (cfDNA). The PaC detection model showed robust potency in distinguishing individuals with PaC from subjects with noncancer with high sensitivity and specificity. However, a few issues need to be discussed. First, the clinicopathologic characteristics of included patients should be considered carefully. Accumulating evidence indicates that there is heterogeneity of distinct PaC types. Most PaCs originate from the exocrine pancreas, with pancreatic ductal adenocarcinoma (PDAC) accounting for approximately 95% of all pancreatic tumors. In contrast to PDAC, the endocrine PaCs (pancreatic neuroendocrine tumors) usually possess a more favorable prognosis. Hence, it is suggested that the pathologic features of the patients with PaC in the current study should be stated more explicitly. Moreover, a large proportion (>50%) of PaC patients with advanced-stage (stages III/IV) were included in the training set. A meta-analysis showed that late-stage cancer patients had higher plasma cfDNA concentrations than healthy controls, prompting the influence of the tumor burden on the amount of cfDNA being released into the circulation.2van der Pol Y. et al.Cancer Cell. 2019; 36: 350-368Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar Based on this, the high proportion of advanced-stage patients might overestimate the sensitivity of the established PaC signal detection algorithm. Second, the study reported that the PaC detection algorithm performed better in early stage cancer detection with a sensitivity of 75.8% and a specificity of 97.4%, compared with carbohydrate antigen 19-9 (CA19-9), which had a sensitivity of 57.6% and a specificity of 95.5%. However, the monitored time points of CA19-9 to detect PaC deserve to be highlighted. Fahrmann et al3Fahrmann J.F. et al.Gastroenterology. 2021; 160: 1373-1383.e6Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar showed that the performance of CA19-9 levels started increasing 2 years before the clinical diagnosis of PaC and sensitivities of CA19-9 for 0.5 to 1 year, 0 to 0.5 years, and 0 to 0.25 years before diagnosis were 24.3%, 60%, and 80%, respectively at 99% specificity. Thus, the acquisition time of plasma CA19-9 samples in this study should be clarified and dynamic continuous monitoring of CA19-9 levels may contribute to the sensitivity improvement and bias reduction. In addition, it is suggested by experts that biomarkers for the early detection of PaC have to possess a very low false-positive rate (<1%) along with a moderate to high true-positive rate (≥60%), or, in other words, sensitivity of at least 60% at a specificity of at least 99%.4Young M.R. et al.Pancreas. 2018; 47: 135-141Crossref PubMed Scopus (38) Google Scholar Wu et al,5Wu H. et al.BMC Med. 2022; 20: 458Crossref PubMed Scopus (8) Google Scholar integrating plasma circulating tumor DNA methylation signatures with CA19-9 for the detection of PaC, found an improvement in the area under the receiver operating characteristic curve (AUC, 0.94), outperforming either methylation signature (AUC, 0.91) or CA19-9 (AUC, 0.89) alone. Therefore, the combination of the current PaC detection algorithm with CA19-9 may improve diagnostic efficiency with a lower false-positive rate and a higher true-positive rate. Third, PDAC develops from well-characterized precursor lesions, including mainly pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN). A recent study revealed that PanIN lesions showed an intermediate methylation level between normal and PDAC, suggesting that PanIN lesions are primed epigenetically for pancreatic carcinogenesis.6Lo E.K.W. et al.Cancer Res. 2023; 83: 1905-1916Crossref PubMed Scopus (4) Google Scholar Further assessment using the established PaC detection test in subjects with PanIN lesions may help identify occult precursor lesions. In terms of IPMN, the PaC algorithm could determine subjects with IPMNs displaying moderate-to-high dysplasia to a certain extent. Liffers et al7Liffers S.T. et al.Gut. 2023; 72: 522-534Crossref PubMed Scopus (8) Google Scholar found that intestinal IPMN had distinct methylation profiles compared with gastric IPMN. However, no significant difference existed in methylated regions between low-grade and high-grade intestinal vs gastric IPMN. Furthermore, the harsh and hypoxic pancreatic tumor microenvironment consisting of tumor cells, stromal cells, immune cells, and extracellular components plays vital roles in PaC tumorigenesis and progression. Various types of cells in the tumor microenvironment may undergo cell death and release DNA to the circulation as the tumor grows. Hence, further identifying tissue or methylation origin cells (eg, 5-hydroxymethylcytosine) profiling using corresponding tissue subtype or cell type markers would decode cancer-related epigenetic distribution examined in cfDNA and improve the accuracy of early detection of PaC. In conclusion, we appreciate the authors for their excellent work, providing meaningful evidence for the early detection of PaC by using epigenomic profiling in cfDNA from plasma. However, it should be noted that additional studies still are needed to address unresolved issues. Ruiyuan Xu: Conceptualization; Writing – original draft; Writing – review & editing. Chengcheng Wang: Funding acquisition, Conceptualization, Writing - review & editing. Yupei Zhao: Funding acquisition, Conceptualization. Epigenomic Blood-Based Early Detection of Pancreatic Cancer Employing Cell-Free DNAClinical Gastroenterology and HepatologyVol. 21Issue 7PreviewEarly detection of pancreatic cancer (PaC) can drastically improve survival rates. Approximately 25% of subjects with PaC have type 2 diabetes diagnosed within 3 years prior to the PaC diagnosis, suggesting that subjects with type 2 diabetes are at high risk of occult PaC. We have developed an early-detection PaC test, based on changes in 5-hydroxymethylcytosine (5hmC) signals in cell-free DNA from plasma. Full-Text PDF Open AccessReplyClinical Gastroenterology and HepatologyVol. 22Issue 3PreviewWe thank Wu et al for commenting on our publication, "Epigenomic Blood-Based Early Detection of Pancreatic Cancer Employing Cell-Free DNA."1 Full-Text PDF